One of the most studied drugs for treatment of cancer is the platinum drug Cisplatin. Cisplatin is a drug with a broad spectrum of activity and is efficient in the therapy of sarcomas, carcinomas and lymphomas to name a few. At the same time, a number of significant disadvantages are associated with this drug. Thus, due to rapid metabolism with formation of inactive protein-bound compounds the drug damages both cancerous and normal cells thereby exhibiting high toxicity, especially nephrotoxicity.
To overcome these problems substantial efforts are put in searching for methods of reduction of toxicity of Cisplatin by means of developing new metalloorganic complexes based on low-molecular organic ligands (U.S. Pat. Nos. 4,169,846; 4,657,927). In this respect, the use of polymeric compounds as chelating or encapsulating agents presents itself as a possible efficient solution of this problem.
US2010/0278925 patent application describes a new type of formulation of organoplatinic compound, comprising at least one organoplatinic compound and at least one associative water-soluble polymer, wherein the said polymer is produced by a polymerization of (Meth)acrylic acid monomers, Urethane monomers and Hemimaleate monomers, and an organoplatinic compound, which is selected from the group of Cisplatin, carboplatin and oxaliplatin. In particular, this invention makes it possible to obtain an oral formulation of the drug in the form of syrup or granulate.
The present invention differs from the above mentioned inventions by using a polymer compound of benzene polycarboxylic acids as a water-soluble polymer to produce organometallic compound preferably for parenteral, enteral and topical application.
Another patent BY6420 describes a polymer-drug formulation of cis-diammineplatinum (II) dichloride exhibiting antitumor effect. Object of the said invention lies in immobilization (encapsulation) of the platinum compound on the surface of 6-carboxycellulose. The resulting drug formulation is used for brain implantation in neurosurgery to prevent recurrence of malignant neoplasms. The said biodegradable polymer-drug formulation of cis-platin exhibits moderate neurotoxicity and improved cytostatic effect.
The present invention differs from the invention disclosed in BY6420 in that the water-soluble polymer of benzene polycarboxylic acids exhibits its own biological effect and that the polymer-drug formulation based on the said polymer can be used for parenteral, enteral and topical application.
In RU 2182482 a process for preparing an anti-cancer agent based on potassium tetrachloroplatinate is disclosed. The said patent discloses a method, in which potassium tetrachloroplatinate reacts with humic compounds. In this method, an aqueous solution of humic substances is treated with a solution of potassium tetrachloroplatinate. The treatment is conducted under irradiation with ultrasonic waves with the power density of 40 W/cm2 and the frequency of 22 kHz for 4 to 8 minutes. The product of the present invention differs from the product described in RU 2182482 by choosing a square-planar coordination compound of platinum (II) as the platinum agent. Moreover, the product of the present invention is produced by using a different method in that the conditions of irradiation are different and that the irradiation power is set per volume of the irradiated product and that the irradiation is performed until the quantity of platinum unreacted with polymer is brought to less than or equal to 25% of the initial quantity and that additionally a thermostating is performed until the quantity of the hydrolysable platinum is brought to less than or equal to 10%. Thereby a different product is obtained. The resulting complex of the present invention is characterized by high stability of bonds and substantially reduced toxicity.
In EP1864673 and RU2368379 another anti-cancer agent is described, which is also produced by reacting coordination compound of platinum (II) with humic compound that is preliminarily subjected to acoustic cavitation caused by exposure to ultrasound with the power density of 0.5 to 5 W/cm3 and the ultrasonic frequency from 18 to 66 kHz. The anti-cancer agent thus obtained is characterized by the content of high-molecular fraction of humic compound of less than or equal to 5%. The product of the present invention differs from the product described in EP1864673 and RU2368379 in that irradiation is carried out until quantity of platinum unreacted with the polymer is brought to less than or equal to 25% of the initial quantity and that additionally a thermostating is performed until the quantity of the hydrolysable platinum is brought to less than or equal to 10%. Thereby a different product is obtained. The resulting complex of the present invention is characterized by high stability of bonds and substantially reduced toxicity.
In RU2183124 a method for producing means protecting an organism against ionizing radiation, namely a substance with radioprotective properties, from materials of natural origin is disclosed. According to this method humic substances are derived from natural raw materials and an aqueous solution of such humic substances is treated with ammonium molybdate. The said treatment with ammonium molybdate is conducted at the temperature of 40±5° C. under irradiation with ultrasonic waves with the power density of 40 W/cm2 and the frequency of 22 kHz for 4 to 8 minutes. The method uses humic substances obtained from oxidized wood lignin. The product of the present invention differs from the invention described in RU2183124 in that the molybdenum salt is selected from a wide range of compounds. Moreover, the product of the present invention is produced by using a different method in that the conditions of irradiation are different and that the irradiation power is set per volume of the irradiated product and that the irradiation is performed until the quantity of molybdenum unreacted with the polymer is brought to less than or equal to 25% of the initial quantity and that additionally a thermostating is performed until the quantity of the hydrolysable molybdenum is brought to less than or equal to 10%. Thereby a different product is obtained. The resulting complex of the present invention is characterized by high stability of bonds and substantially reduced toxicity.
In EP1864674 and RU2350353 another method of producing an agent protecting an organism against ionising radiation is disclosed. This agent is prepared by treating an aqueous solution containing humic substances and ammonium molybdate with wave radiation. The content of ammonium molybdate is selected in the range up to 0.4 parts by weight per 1 part of humic substances, the treatment is conducted until the high molecular fraction of humic substances is brought to the level of less than or equal to 5%. The product of the present invention differs from the invention described in EP1864674 and RU2350353 in that the molybdenum salt is selected from a wide range of compounds. Moreover, the product of the present invention is produced by using a different method in that the conditions of irradiation are different and that the irradiation is performed until the quantity of molybdenum unreacted with the polymer is brought to less than or equal to 25% of the initial quantity and that additionally a thermostating is performed until the quantity of the hydrolysable molybdenum is brought to less than or equal to 10%. Thereby a different product is obtained. The resulting complex of the present invention is characterized by high stability of bonds and substantially reduced toxicity.
Besides the benefits, compositions described in RU2182482, EP1864673, RU2368379, RU2183124, EP1864674 and RU2350353 have a number of disadvantages caused by the fact that organic ligands, which they incorporate, are characterized by variable composition, safety and biological activity and, as a consequence, cannot be used in the development of stable complexes or composite substances suitable for preparation of pharmaceutical, nutraceutical or cosmetic compositions.
The inventors of the present invention have surprisingly found that a novel water-soluble polymer compound of benzene polycarboxylic acids, characterised by low content of mineral and low-molecular impurities and own biological activity can be used for development of stable, safe and potent organometallic complexes.
Improved stability of bonds between the polymer and metal cation in such complexes is achieved through introduction of polymerization, purification and thermostating operations and use of new ultrasonication conditions when the power is set per volume and the treatment is continued until complex is formed with more than 75% of the metallic compound. Thereby a different product is obtained.
The present invention also discloses composite substances based on the new water-soluble polymer compound of benzene polycarboxylic acids, in which the said polymer compound acts as a complexing and/or encapsulating agent forming low-toxicity highly efficient complexes with high-stability bonds. Even in low concentrations these new composite substances show high efficiency. Such composite substances comprising, for example, platinum and molybdenum complexes, demonstrate promising properties. The platinum complexes act as efficient anti-cancer agents and experimental results demonstrate their improved ability to kill cancer cells when compared to the prototypes and such known anticancer agents as Cisplatin and Carboplatin. The molybdenum complexes act as efficient agents for prophylaxis and treatment of diseases caused by cell cycle disruption, which result, for instance, from radiation exposure, cell aging or immune disorders. The pharmaceutical compositions of the present invention can also be used in reducing/minimizing side effects resulting from conventional radiotherapy or chemotherapy.
Chemical properties of the new water-soluble polymer compound of benzene polycarboxylic acids make it possible to obtain a broad range of highly stable complexes, as well as pharmaceutical, nutraceutical and cosmetic compositions for parenteral, enteral and topical administration to human beings and animals.